Abstract / Summary
Abstract Major depressive disorder (MDD) is associated with immune dysregulation and altered glial biology, yet the molecular relationships between peripheral and central transcriptional changes remain incompletely understood. Here, we integrated ten transcriptomic datasets spanning human peripheral blood, human and macaque brain single-cell transcriptomes, and rat pharmacological models to identify cross-tissue molecular patterns associated with MDD. Reproducible transcriptomic feature was identified across cohorts, and its genes showed preferential expression in microglia and oligodendrocytes, indicating convergence of peripheral MDD-associated transcriptional changes with glial-associated molecular programs. Up-regulated genes were preferentially expressed in microglia, whereas down-regulated genes were enriched in oligodendrocytes and related to inflammatory and myelination-related pathways. Multi-layer integration further prioritizes ANO10, HK2, and CCDC50 as candidate dysregulated genes. Among these, HK2 showed the most consistent evidence across peripheral cohorts, brain cell types, pharmacological models, and preliminary clinical validation, supporting its prioritization as a candidate immunometabolic biomarker for further investigation. Together, these findings define a glial-associated immunometabolic framework for MDD and identify peripheral blood transcriptional biomarkers associated with the neuroimmune molecular landscape of the disorder.